Buprenorphine and/or a salt thereof is a non-narcotic analgesic which has an analgesic efficacy about 30 times higher than that of morphine and 75 times higher than that of pentazocine and is broadly used in order to relieve cancerous pain and postoperative pain and to assist narcotic drugs. Since buprenorphine and/or a salt thereof sometimes generates side effects such as nausea, emesis, respiratory depression and the like, its use requires the greatest care. In consequence, great concern has been directed toward the development of a dosage form which, when buprenorphine and/or a salt thereof is administered, can prevent too much increase in the blood drug level and control dosage of the drug.
On the other hand, percutaneous administration, which has been vigorously studied recently, has a number of advantages. For example, (1) it is expected that the percutaneous administration achieves a drug effect lasting for 24 hours or longer, which makes such frequent administration unnecessary as required in the cases of injections, sublingual tablets and suppositories, (2) it is expected that the percutaneous administration makes absorption uniform and thus excessive administration can be avoided, and side effects therefore can be relieved, (3) the percutaneous administration neither causes any unevenness in the absorption/retention in the digestive tracts nor experiences first pass effect in the liver and (4) the percutaneous administration is applicable even to a patient whom oral administration is impossible.
However, buprenorphine and/or a salt thereof is extremely poor in percutaneous absorption and thus can be hardly absorbed from the skin in a required dose at a practically available adhesion area, i.e., 100 cm.sup.2 or less.
In consequence, many attempts have been made to develop a percutaneous absorption preparation of buprenorphine and/or a salt thereof which has many advantages as described above (for example, see JP-A-2-191214, JP-A-3-163014, JP-A-3-193732, JP-A-4-217926 and U.S. Pat. No. 5,069,909; the term "JP-A" as used herein means an "unexamined published Japanese patent application").
However, most of these preparations appear to have difficulty in formation thereof or cause adhesive residue and not to be usable in practice, since the skin penetration of a drug is discussed in the form of a solution or a percutaneous penetration enhancer is merely added to a pressure-sensitive adhesive without any special idea. Furthermore, as the percutaneous penetration enhancer contained in these preparations comprises an organic acid, there are some problems from the viewpoint of safety such as generation of skin irritation.
When a percutaneous penetration enhancer is added in order to improve the percutaneous absorption of buprenorphine and/or a salt thereof, the percutaneous penetration enhancer sometimes oozes out to the surface of a plaster during storage, thus changing the properties of the preparation. Further, the addition of a plasticizer or a percutaneous penetration enhancer to the pressure-sensitive adhesive causes a decrease in the cohesive force and, as a result, adhesive residue is formed or stringiness is generated when the preparation is adhered to the skin.
As means for resolving these problems, various methods have been proposed, such as a method in which fine powder silica is added to a pressure-sensitive adhesive (JP-A-2-295565; the term "JP-A" as used herein means an "unexamined published Japanese patent application") or a method in which pressure-sensitive adhesive characteristics are controlled by making an ointment base into gel form through crosslinking of a pressure-sensitive adhesive (JP-A-3-220120).
However, the method in which fine powder silica is added cannot improve pressure-sensitive adhesive characteristics in some cases depending on the formulation composition and formulation method of pressure-sensitive adhesives. Particularly, when a polar substance such as polyethylene glycol is added in a large amount as a percutaneous penetration enhancer, decrease in the viscosity of pressure-sensitive adhesives cannot be prevented.
On the other hand, the method in which entire portion of a pressure-sensitive adhesive is crosslinked by external crosslinking to make it into gel form is markedly excellent in view of the point that the pressure-sensitive adhesive characteristics can be controlled even when a percutaneous penetration enhancer and other additives are used in a large amount.
This method, however, also cannot be used in the case where the percutaneous absorption preparation contains a substance having a crosslinking inhibition action, because the pressure-sensitive adhesive cannot fully be crosslinked. In particular, when a generally and frequently used polyfunctional isocyanate is used as a crosslinking agent, addition of a drug or additive having a hydroxyl group, an amino group, a carboxyl group or a mercapto group to the pressure-sensitive adhesive causes crosslinking inhibition. For the reason, the drugs and additives having these functional groups cannot be used.
In addition, techniques in which a percutaneous absorption preparation is produced by making a pressure-sensitive adhesive into granular form are disclosed, e.g., in JP-B-58-12255 (the term "JP-B" as used herein means an "examined Japanese patent publication") and JP-B-58-23367, but these techniques have a difficulty in obtaining appropriate pressure-sensitive adhesive characteristics in the case where a percutaneous penetration enhancer and other additives are used in a large amount.